High central D2-dopamine receptor occupancy as assessed with positron emission tomography in medicated but therapy-resistant schizophrenic patients

Coppens, H.; Slooff, C. J.; Paans, Anne M. J.; Wiegman, T.; Vaalburg, W; Korf, Jakob

doi:10.1016/0006-3223(91)90132-6

Cited by 72 publications

(24 citation statements)

References 14 publications

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“…It is, of course, well known that many schizophrenia patients may not clinically improve despite high occupancy (Ͼ75%) of their D2 receptors. [78][79][80][81] This supports the long-standing assumption that there may be more than one subtype of schizophrenia.…”

Section: Is D2 Block a Necessary Minimum For Antipsychotic Action?supporting

confidence: 66%

Antipsychotic drugs which elicit little or no Parkinsonism bind more loosely than dopamine to brain D2 receptors, yet occupy high levels of these receptors

1998

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This review addresses two questions. First, why does clozapine apparently occupy low levels of dopamine D2 receptors in patients, in contrast to all other antipsychotic drugs which occupy 70-80% of brain dopamine D2 receptors? Second, what is the receptor basis of action of antipsychotic drugs which elicit low levels of Parkinsonism?Antipsychotic doses of clozapine occupy between 0% and 50% of D2 receptors, as measured in patients by a variety of radioligands. It has recently been found, however, that the percent occupancy of a receptor by a drug depends on the radioligand used to measure that receptor. Based on this new finding, this review concludes that clozapine clinically occupies high levels of D2 receptors in the absence of any radioligand. This occupancy is estimated to be of the order of 70-80% in the dopamine-rich region of the human striatum, and even higher in the limbic D2-containing regions which are low in endogenous synaptic dopamine. This conclusion arises from two different approaches. One approach is to relate the reported clozapine occupancies in the human striatum with the dissociation constants of the various radioligands at the D2 receptor. This relation extrapolates to approximately 70-80% occupancy by clozapine when clozapine competes with endogenous dopamine at the D2 receptor. The second approach is to calculate the D2 occupancy of each antipsychotic drug, using the average spinal fluid concentration and the correct dissociation constant of the antipsychotic, thereby revealing that all antipsychotic drugs, including clozapine, occupy approximately 70-80% of dopamine D2 receptors in the human striatum, and possibly higher in the limbic regions.As determined by the new dissociation constants, antipsychotic drugs which elicit Parkinsonism (trifluperazine, chlorpromazine, raclopride, haloperidol, fluphenazine, risperidone) bind more tightly than dopamine to D2, while those antipsychotic drugs which elicit little or no Parkinsonism (melperone, seroquel, perlapine, clozapine, remoxipride, molindone, sulpiride, olanzapine, sertindole) bind more loosely than dopamine to D2 receptors. Compared to the tightly bound antipsychotic drugs, the more loosely bound antipsychotics generally require higher clinical doses, require fewer days for clinical adjustment, but may dissociate from the D2 receptor more rapidly and could lead to clinical relapse somewhat earlier than that found with the traditional tightly bound antipsychotic drugs.

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Section: Is D2 Block a Necessary Minimum For Antipsychotic Action?supporting

confidence: 66%

Antipsychotic drugs which elicit little or no Parkinsonism bind more loosely than dopamine to brain D2 receptors, yet occupy high levels of these receptors

1998

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“…The research strategy developed from these initial studies represents the most direct, noninvasive method available to measure neurotransmitter concentrations in the living brain. In the case of schizophrenia, the potential importance of studying dopamine concentrations rather than receptor density is supported by the evidence that 1) schizophrenic patients do not consistently show alterations in dopamine receptor numbers in comparison with normal control subjects (1-3); 2) the degree of striatal D 2 receptor occupancy by antipsychotic medications is not indicative of therapeutic response to antipsychotic treatment (10,11); and 3) the time course of occupancy of the striatal D 2 receptor is much more rapid (several hours) than the time course of clinical response (several weeks) (12,13). Therefore, in vivo ligand-binding measurements of the striatal D 2 receptor in isolation suggest that symptoms and response to treatment may be related to other factors, such as the integrity of extrastriatal dopamine systems or the ability of other functionally linked neurotransmitter systems to modulate dopamine function or to be modulated by dopamine.…”

mentioning

confidence: 93%

Serotonergic modulation of dopamine measured with [11C]raclopride and PET in normal human subjects

Smith

Dewey²,

Brodie³

et al. 1997

AJP

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“…However, the results were controversial and have been the subject of continued debate with respect to differences in methodology and subject characteristics (3,4). Therefore, the need to further study mechanisms that regulate synaptic dopamine activity is supported not only by the evidence that schizophrenic patients may or may not show significant changes in dopamine receptor number (Bmax) from normal controls but by the fact that the degree of striatal D2 receptor occupancy is not indicative of response to neuroleptic treatment (5,6). As a result, a series of PET studies using a multiple mechanistic approach, including an examination of the interactions that have been shown to exist between acetylcholine and dopamine, have demonstrated that the binding of labeled N-methylspiroperidol (NMSP) (7) and raclopride, radiotracers used in these early studies, is sensitive to changes in synaptic dopamine concentrations (8)(9)(10)(11)(12).…”

mentioning

confidence: 99%

Effects of central cholinergic blockade on striatal dopamine release measured with positron emission tomography in normal human subjects.

Dewey

Smith

Logan

et al. 1993

Proc. Natl. Acad. Sci. U.S.A.

121

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Previously we demonstrated that positron emission tomography (PET) can be used to measure changes In the concentrations of synaptic dopamine and acetylcholine. Whether induced directly or indirectly through interactions with other neurotransmitters, these studies support the use of PET for investigating the functional responsiveness ofa specific neurotransmitter to a pharmacologic challenge. In an extension of these findings to the human brain, PET studies designed to measure the responsiveness of striatal dopamine release to central cholinergic blockade were conducted in normal male volunteers using high-resolution PET and Neurotransmitter receptor studies using functional imaging techniques including positron emission tomography (PET) and single photon emission computed tomography initially examined single neurotransmitter systems in human and primate brains. For example, the first application of these techniques to neuropsychiatric disease addressed one important component of the dopamine hypothesis of schizophrenia (1, 2). However, the results were controversial and have been the subject of continued debate with respect to differences in methodology and subject characteristics (3, 4). Therefore, the need to further study mechanisms that regulate synaptic dopamine activity is supported not only by the evidence that schizophrenic patients may or may not show significant changes in dopamine receptor number (Bmax) from normal controls but by the fact that the degree of striatal D2 receptor occupancy is not indicative of response to neuroleptic treatment (5, 6). As a result, a series of PET studies using a multiple mechanistic approach, including an examination of the interactions that have been shown to exist between acetylcholine and dopamine, have demonstrated that the binding of labeled N-methylspiroperidol (NMSP) (7) and raclopride, radiotracers used in these early studies, is sensitive to changes in synaptic dopamine concentrations (8-12). Both raclopride and NMSP are used as PET imaging agents for postsynaptic dopamine D2 receptors.PET's sensitivity for detecting alterations in labeled raclopride or NMSP binding has been demonstrated by pharmacologic agents that selectively increase or decrease synaptic dopamine concentrations by neurochemically different mechanisms (8, 9). These findings suggest that this experimental approach is well suited for studies designed to investigate disease states that begin with or result from a loss in the ability to adequately regulate synaptic dopamine release. Furthermore, the potential for this experimental approach clearly extends beyond the ability to measure changes in a single neurotransmitter system after a specific pharmacologic challenge. As it is well known that neurotransmitter systems do not work in isolation, we have extended these studies to include an examination ofthe utility ofPET for noninvasively assessing neurotransmitter interactions in the human brain.Neurotransmitter interactions have been demonstrated anatomically, physiologically, and beha...

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High central D2-dopamine receptor occupancy as assessed with positron emission tomography in medicated but therapy-resistant schizophrenic patients

Cited by 72 publications

References 14 publications

Antipsychotic drugs which elicit little or no Parkinsonism bind more loosely than dopamine to brain D2 receptors, yet occupy high levels of these receptors

Antipsychotic drugs which elicit little or no Parkinsonism bind more loosely than dopamine to brain D2 receptors, yet occupy high levels of these receptors

Serotonergic modulation of dopamine measured with [11C]raclopride and PET in normal human subjects

Effects of central cholinergic blockade on striatal dopamine release measured with positron emission tomography in normal human subjects.

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